Abstract [en]

Aim: To study if families with hemophilia B in Sweden carrying the same mutation are identical by descent (IBD) or the result of independent mutations (RM).

Study group: A total of 77 presumed unrelated and unselected Swedish families with hemophilia B comprising all clinical severities (total and large deletions not included). Control group of 256 healthy individuals.

Methods: Haplotyping was performed using 90 SNP markers (11 within the F9 gene) and 1 microsatellite marker. The frequencies of shared haplotypes were determined in the control group, and the ages of the shared haplotypes will be determined using the program ESTIAGE.

Results: Analysis of the mutations gave the following results: 5 small deletions (<10bp), 2 small insertions (<10bp), 3 splice site mutations, 14 nonsense mutations, and 53 missense mutations. A total of 30 mutations (39%) occurred in a single individual only, whereas the remaining 47 mutations occurred in 2 or more individuals; 7 mutations occurred in 2 individuals, 4 mutations occurred in 3 individuals, 2 mutations occurred in 4 individuals, 1 mutation occurred in 6 individuals, and 1 mutation occurred in 7 individuals each, i.e., 47 mutations out of 77 (61%) were either IBD or recurrent mutation. Haplotyping and comparisons with the control group classified 21/47 mutations as IBD and 25/47 as RM. The phenotypes of the 21 IBD individuals were mild (17), moderate 2), and severe (1); those of the 25 RM individuals were mild (7), moderate (7), and severe (12). Age estimation of the mutations is ongoing.

Conclusion: Many families with hemophilia B, in particular those with milder forms, carrying the same mutation are IBD, i.e., revision of ‘‘hot-spots’’ for mutation is needed.